Cell kinetic studies after high dose Ara-C and adriamycin treatment in a slowly growing rat leukemia model (BNML) for human acute myelocytic leukemia.

The effect of high-dose cytosine arabinoside (Ara-C; 1-beta-D-arabinofuranosyl cytosine) injections (200 mg/kg i.v.) on cell cycle perturbation was investigated in a slowly growing rat leukemia (BNML) which is a realistic model for human acute myelocytic leukemia. Flow cytometric analysis showed an initial decrease of cells in S phase from 26 to 13% and a subsequent accumulation of up to 50% at 10-14 h after injection. The low number of S phase cells during the first 8 h might be due to a combination of cell kill in S phase and a block at the G1/S boundary. The results make it very likely that the origin of the accumulated S phase cells is the resting compartment and that these recruited cells enter the proliferation phase as a synchronized cell population. By repeating the Ara-C injection at the time of accumulation of cells in S phase, a similar synchronized wave of recruited cells to that after the first Ara-C injection was observed. Flow cytometric analysis after Adriamycin (7.7 mg/kg i.v.) treatment, which has been shown to be cytotoxic for BNML cells, showed no changes in cell cycle distribution. It was concluded that Adriamycin might have the same toxicity for cells in all of the different cell cycle phases. The application of these data with respect to effective tumor load reduction is discussed in a second report.